Breathing is a remarkable behavior that regulates gas exchange to support metabolism and regulate blood pH. Failure to breathe properly in humans suffering from disorders such as sleep apnea, apnea of prematurity, congenital central hypoventilation syndrome, Rett Syndrome, central alveolar hypoventilation, and perhaps sudden infant death syndrome, leads to serious adverse health consequences, even death. If these pathologies are to be understood, the site(s) and mechanisms of respiratory rhythmogenesis must be revealed. Our laboratory, through support of this and related NIH grants, have contributed in important ways to our current understanding of the control of breathing. We made two novel discoveries in the previous grant period: 1. Partial lesions of the preBotzinger Complex (preBotC) in adult rats causes sleep disordered breathing. We will exploit this model of central sleep apnea to address an important question of considerable clinical relevance: What can be done to reduce the severity of central sleep apnea? Can drugs affecting serotonin, noradrenergic, cholinergic or specific peptide neurotransmission affect central sleep apneas when directly applied to the preBotC? If so, this will provide important information about possible causes of central sleep apnea and of the state-dependent role of the preBotC in generation of breathing pattern. 2. Respiratory rhythm generation appears to involve two distinct anatomically separated oscillators: the preBotC and the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). We will look at mice (Krox20) with genetically-induced brainstem developmental anomalies that affect the RTN/pFRG. If our hypotheses are correct, we should see profound changes in expiratory-related activity. A complementary approach will be to record single neuron activity in the RTN/pFRG of rats. We predict we will observe rhythmically active RTN/pFRG when there is active expiratory motor output. These experiments, regardless of outcome, will help us to better understand RTN/pFRG function in normal and pathological states and under different experimental conditions and its interactions with the preBotC. The investigation and testing of the novel hypotheses arising from our recent discoveries should have fundamental impact on our understanding of breathing in humans in health and disease